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Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine. All content is Derek’s own, and he does not in any way speak for his employer.

But there’s a lot of activity going on with tau these days. Merck just announced that they’re buying the rights to Teijin Pharma’s tau antibody therapy, which has gotten some attention. AC Immune has a deal with J&J on a tau antibody program of their own, and AbbVie is going into Phase II with an anti-tau antibody as well (also inlicensed). Bristol-Myers Squibb had another anti-tau program going, but that one has just been licensed to Biogen. On the small-molecule end of things, that first link in the paragraph details a number of attempts at kinase inhibitors (to slow down tau hyperphosphorylation) and small-molecule aggregation inhibitors (which is where TauRx came to grief).

It’s unfortunately going to be quite a while before we see what any of the agents do – such is the course of Alzheimer’s in the clinic. I have no idea what the prospects are, but it would appear that several companies have decided that another crack at amyloid is not the way to go. Considering the relentless string of brutally expensive failures in that area, they probably have a point. In this case, better the devil you don’t know than the one that you’ve come to know too well.

Update:as suggested here, what the tau trials will have to avoid is wishful thinking. That paper suggests that some of the previous amyloid antibody trials never should have gone as far as they did:

An analysis of publicly available data from the Phase II studies for bapineuzumab and solanezumab indicates that neither compound produced compelling evidence of drug-like behavior that would justify their progression into pivotal trials. The published data suggest that sponsors took decisions to move these compounds into Phase III on the basis of vastly limited data that were rife with type I error and probably driven by commercial concerns.

Probably, indeed. There are moral hazards in this area, all of which can be sold to oneself as trying to do everything one can to help patients.

60 comments on “A Movement Towards Tau in Alzheimer’s?”

You knew that I would not be far behind. The movement away from amyloid to tau likely marks a sidestep rather than an advancement. Reducing tau hyperphosphorylation or increasing the dephosphorylation of tau may improve neurotrasmissions but it is unclear if it would do anything else.

There are two pathways to tau hyperphosphoryation–one is via calpain; the second is via the inhibition of the phosphatidylinositol 3-kinase/Akt pathway due to nitration.

The inhibition of the phosphatidylinositol 3-kinase/Akt pathway results in a series of other problems including reduced blood flow in the brain, and a steep decline in neurogenesis and synaptogenesis.

Nitration and oxidation rather than the misfolding of amyloid and tau are likely the keys to Alzheimer’s disease. When peroxynitrite is scavenged it produces water and water is a putative de-nitrating agent. Peroxynitrite scavengers through hydrogen donation also partially reverse oxidation. One more paradigm shift (beta amyloid–hyperphosphorylated tau–nitro-oxidative stress) is probably needed before the effective treatment of Alzheimer’s disease is possible.

Your better bet is to use peroxynitrite scavengers that can generate sufficient water in and around neurons. The chemistry is rather simple using hydrogen donating compounds: ONOO- + 2H+ + 2e-= NO2- + H20 (peroxynitrite scavenging) and Protein-tyrosine-NO2+H20=Protein tyrsoine-H + H+ + NO3- (tryosine de-nitration). If nitration and oxidation are at the heart of Alzheimer’s disease then the next step is to find compounds that are excellent hydrogen donors. Among the best are methoxyphenols:

“Moreover, the antioxidant activity of curcumin increases when the phenolic group with a methoxy group is at the ortho position. The orthomethoxy group can form an intramolecular hydrogen bond with the phenolic hydrogen, making the H-atom abstraction from the orthomethoxyphenols surprisingly easy.”

The problem with curumin is that it is not well absorbed into the bloodstream (although its absorption can be increase in a number of ways–the easiest being the use of black pepper).

Korean red ginseng contains two methoxyphenols: ferulic acid and syringic acid (along with a series of other polyphenolic antioxdiants). An open label trial (always subject to criticism) produced the following results.

“A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

As chemists you can likely develop even better compounds to partially reverse nitro-oxidative stress.

My mantra is that all the risk factors for Alzheimer’s disease increase peroxynitrite formation (including amyloid beta), the putative preventive measures for Alzheimer’s disease reduce peroxynitrite formation, peroxynitrite formation is directly or indirectly responsible for all the features of the disease, and the only compounds that have partially reversed Alzheimer’s disease are peroxynitrite scavengers. The argument could be incorrect, but there is considerable evidence to support it.

Here’s yet another intriguing idea in this field which does not involve either amyloid or tau as primary mechanisms. Instead it postulates that the immune system (complement, microglia) have a role in neonatal brain development by pruning dendrites, and inappropriate reactivation of these microglia later in life leads to immune mediated “pruning” which can result in neurodegenerative diseases.https://stevenslab.org/research/

Substitute microglia for t cells and the same thing likely happens in Alzheimer’s disease. However, while decreasing microglia activation may be beneficial during the early stages of Alzheimer’s disease, trying to increase immune response during the later stages of the disease is likely to be unproductive since removing plaques does little to no good.

I poorly worded the last sentence–the first part of the sentence refers to labs seeking to curb inflammation in Alzheimer’s disease (of which researchers proposing the over-pruning of synapases hypothesis belong). The second part of the sentence refers to labs working in the complete opposite direction. My thought is that neuroinflammation is biphasic in Alzheimer’s disease: high during the early stages of the disease and lower as the disease progresses. This may in part explain the lack of effectiveness of non-steroidal anti-inflammatory drugs against Alzheimer’s disease.

We’ve had millions of people on chronic NSAIDS for decades now. If Alzheimer’s were an inflammatory problem or involved an inflammatory component (and if NSAIDS penetrate the brain in useful concentrations) we would expect to seen reduced incidence of Alzheimer’s in this population. That dog hasn’t barked

I still don’t think the amyloid hypothesis has been properly tested. You will need to treat people years before they have symptoms. Genentech/Roche are doing this in the prodromal Columbia study. If those results are negative, that should be the nail in the coffin, so to speak.

Beta amyloid is only one source of oxidative stress so removing it only slightly slows down the early progression of the disease (as numerous clinical trial results have shown) and may only buy a few years in terms of the onset of the disease.

The families with the paisa presenilin-1 gene mutation in Colombia develop Alzheimer’s disease on average a decade earlier than the individuals with the same gene in Japan. One of the differences is that the Colombian families live in one of the most mercury-contaminated regions in the world.

Remove multiple sources of oxidative stress (including beta amyloid) and you can perhaps slow down the onset of the disease by a decade or more. Another option early on is to partially inhibit protein kinase C which is a key enzyme leading to oxidative stress in Alzheimer’s disease.

“Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

The supposed main actors in Alzheimer’s disease (beta amyloid and hyperphosphorylated tau) are likely side contributors. Instead, there is a very close correlation (or causation) between oxidative stress, the depletion of glutathione–the brain’s master antioxidant, and the onset and progression of Alzheimer’s disease.

I believe that the Merck/Schering compound (verubecestat) is in a prodromal study that will read out in the not-too-distant future. The last I looked, that was likely to be the first of the “last nails” – the other being the Biogen antibody (aducanumab) that targets aggregated A-beta.

There seems to be a little of the “I’m not dead yet” sentiment in the amyloid community, still. However, verubecestat seems like the first time we have been able to get data with a really good compound, and this next test of the amyloid hypothesis with that compound seems like it will be truly telling.

For any who have spent time in these particular trenches, this is a remarkable accomplishment in and of itself.

This is a strange choice for Perlmutter, SVP of R&D at Merck. There’s no human genetic evidence linking the Tau Gene to AD proper. Further, Perlmutter canned the Amyloid Ab candidate at Amgen, presumably because he didn’t buy into the Ab for brain disease concept. Sadly, “commercial concerns” seems about right here.

Well, you are welcome to your opinion. You should be very pleased to know that those same “mofos” you are lambasting have actually developed numerous CNS agents that might help you with your personality deficit.

It’s starting to be evident that a lot of modern science relies on compliance of the younger folks with their supervisor’s ideas which in turn are highly influenced by the funding system to keep investors and/or NIH happy. These are merely ideas to trim branches off a huge tree rather than cut it off from the stump. Sure, you can design small molecules to do wonderful things like even inhibiting protein protein interactions but at the end of the day, you are not treating the root cause of the disease. You are paid only to prune it and make it look like you cured it when in reality there is absolutely no cure for these diseases even with the whole genome editing crap. Cancer and neurodegenerative diseases are here to stay until the end of the human species unless you have figured out how to control evolution in a large population. Easier said than done!

I cant agree with your obscenities and I like Lowe a lot. However, I agree with the spirit. If the shoe was on the other foot–established chemists ( like lowe , but not lowe ) commenting on new ideas from “students” on a blog– they would be dismissive ad nauseum. Today’s professors hate students, particularly those with new ideas.

I’m surprising myself by replying to such a rude post. Despite that, I feel the need to point out that some forms of cancer are already curable; some kinds of testicular cancer, leukemia, and thyroid cancer in particular. So there’s hope for other kinds as well.

You may or may not be right about neurodegenerative disease. I believe that’s where much of the hope for stem cells comes from.

Cancer deaths are on the decline. Mortality from colon and rectum cancer, for instance, declined by 35.5% just over the past few decades.

What’s more, average 5-year survival post-diagnosis has risen quite dramatically (on average) over the past couple decades, for virtually all types of cancer.

There are a few confounders that the study doesn’t take into account, like the decline in smoking rates, but I think that modern medicine is helping cancer patients, and that this is sufficiently clear in the data.

This is, if anything, despite the best efforts of the FDA — without which we’d surely have better polypharmacological weapons at our disposal, and cancer patients would have access to experimental drugs that might help. Without them, we’d fight the war on cancer as though it were a war, and I’m confident that the disease would be in a full rout by now. Still, the situation at present is not too bad, and it’s getting better all the time.

As for there being no cure for neurodegenerative diseases… that surely depends on whether this degeneration is just inherently associated with aging, which is very poorly understood, or whether it is associated with some form of pathology. Many neurodegenerative diseases seem to be, at least superficially, the latter.

You’ll see bumps in diagnoses when earlier diagnosis criteria are implemented and you’ll clearly see the decline in lung cancer diagnoses as smoking declines. You’ll see improved survival which is independent of reduced diagnoses. You’ll even see a levelling off in diagnosis of testicular cancer that correlates with the levelling off in the decline of sperm quality (for the Danish data set and you’ll have to find the sperm quality data elsewhere).

A small plea here for people to keep an open mind on AD pathogenesis and consider the cell cycle theory. It links so much of the data. In brief, the neurons affected by AD do not, in healthy adult patients, undergo cell division but in AD patients the cell cycle G1/S checkpoint is incompetent and the normal process of synaptogenesis, which involves a neuron shuttling from G0 to G1 to make use of the early cell cycle machine to remodel itself, results in the neuron irreversibly passing into S and then G2 phase. G2 phase is a very distinct metabolic state that is ordinarily transient. Maintained indefinitely, it results in intracellular tau polymerisation and extracellular Abeta formation, because in G2 in ordinary cells (1) the tau cytoskeleton is disassembled and phosphorylation is upregulated and (2) amyloid processing is altered. Tau and amyloid are downstream symptoms of an upstream cell cycle dysregulation. The G2 neuron is also in an altered metabolic state and vulnerable to stressors, oxygen deprivation etc. There is something here for everyone!

And there are! All sorts of reports, showing lower AD risk in patients on various drugs with cell cycle side effects. Thank heaven for dirty blockbusters like statins.

The most interesting is Aricept, if you shift your frame of reference. ACh has a cell cycle signalling role as well as a neurotransmitter role and data suggest that AChE inhibition shows symptomatic relief through cytostatic effects of modifying this pathway. However, the cell cycle pathway in question is broken in the largest sub-population of AD, by cell cycle dysregulation SNP analysis, so the drug struggles to show efficacy without stratification tools.

PS: There are not main headline cytostatic drugs with the right profile, of mild G1/S up-regulation, no apoptosis and chronic administration. Most oncology regimes are right out (G2, apoptosis, acute dosing) and many others too. Immunosuppression may be a good place to look, e.g. Rapamycin, which is the workhorse of the AD cell cycle lab science.

Here s a novel thought–maybe a complex disease like non-genetically predisposed AZ is caused by or than just a simple protein or two (or dozen). Reductionism in science and medicine has been both a blessing and a curse.

Here is my 2ct. Human genetics proves amyloid role in AD. But amyloid is not drugable with current mAb technology or small molecules ; sadly. New approach is needed, but alas VC and Pharma are fundamentally stuck WRT AD, so they go after Tau as the next logical target. Can someone say with a straight face these anti-Tau mAbs have any chance? Anti-tau mAbs have to do acrobats that Anti amyloid mAbs do, plus they have to get across membrane of cell, in the right part of the brain, whack the tau and get away clean. Famous words of Spongebob Squarepants.. “goood luck with that!”

Honestly I commend the effort and thank the people willing to stake career and cash on it.

But seriously. A new approach is needed. Every year 60k people descend on SFN meeting to talk Neuro and no one has a solution to AD.

So many people chasing the same stories. What a waste of talent.

Please everyone be willing to consider alternative approaches to getting at the problem. I don’t presume to know precisely what the alternatives are, but it seems that pursuing re growth of neurons is a ripe area.

I wholeheartedly concur. I made a response to another post on amyloid and genetics yesterday, but I forgot that links apparently don’t go through over the weekend. If a duplicate of my previous comment appears on Monday I apologize in advance.

The amyloidist mistakenly asserted that amyloid is the cause of Alzheimer’s disease rather than a contributing factor to Alzheimer’s disease. All of the genetic mutations that lead to early onset Alzheimer’s disease cause oxidative stress, but again so do many other factors.

Early Onset Alzheimer’s Disease and Oxidative Stress

“The neurodegenerative process that occurs in AD involves a specific nervous cell dysfunction, which leads to neuronal death. Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology.”

One can plausibly argue that mutations increasing amyloid production are a bigger factor in oxidative stress in early onset cases than in late onset cases, but otherwise it is the same disease. Depending on what other stressors a person is exposed to, anti-amyloid drugs may slow down the onset of Alzheimer’s disease, but inhibiting the pathway that leads to oxidative stress would likely be more effective. In addition if you reduce oxidative stress, you increase neurogenesis.

I don’t think the anti-tau approach is going to work better than the anti-amyloid approach either. Try a new approach and see if you get a new result.

Has anyone here floated the idea that all of modern science is a sham? Any rebukes are welcome. On the other hand, our obsession with a small handful of fundamental concepts (eg. DNA, proteins, molecular theory of chemistry, etc.) is hard to justify given our apparent knowledge of the vast complexity of disease.

Honestly, the number of permutations of DNA possible isn’t even that impressive. 3 DNA nucleotides only have 64 possible permutations for a codon. 3 amino acids can only be arranged in 27 different ways. If you move up to six peptides you’ll be able to achieve 6.4×10^7 possibilities, but compare the DNA code to an example of a post-translational modification like glycosylation. 3 sugars alone that are used in biology to modify proteins can produce over 38,000 possible permutations. The number of hexapeptides possible (6.4×10^6) is orders of magnitude smaller than the number of ways 6 carbohydrates used in biology can be arranged (which is over 10^15).

There’s almost a quantum level of information hidden in something like the glycome, which is massively orders of magnitude more complex than the genetic code. And worse yet, other post-translational modifications exist on top of other post-translational modifications like glycosylation. Scientists are already familiar-those sulfo patterns on a molecule like heparin are absolutely critical. Biology absolutely is sensitive to to something like the glycome and can decipher its code. Change one sugar on an ion channel and you completely alter its gating physics. Change a sugar on Tau, you can alter its hyperphosphorylation pattern. One of the first lines of defense of the immune system is recognition of foreign sugar epitopes. Cancer? Aberrant sugars hat allow them to hide from immune surveillance.

The worst part is that something like the sugar code doesn’t have a template we can manipulate to study like DNA does with proteins. And that’s only one single class of PTM. There are even more mind benders like non-enzymatically controlled PTM modifications of proteins.

All I’m saying is that there’s​ an entire, massively complex level of biology thats like dark matter over our understanding of life through DNA. Life and disease might be doing a lot of cool stuff through DNA, but reductionism has pigeonholed us for decades into focusing on life and disease through a template driven lens.

What if complex diseases like AZ are more than the sum of its genetic anomalies? Where do we go from then? And how do you find and screen a drug target if your problem is a systems problem rather than a target problem? I suppose going back to the whole phenotypic screening idea would work….

It is basic to information theory that any message can be carried in any sufficient code. Just as you can convey e.g. the MonaLisa in binary, with none of the many variations in hue, and line width, and texture…of tempura paints.
Yes, some codes will be terser than others. But that does not imply that they’re used to convey more.

Except in biology those differences in hues for the Mona Lisa are important. A better analog would be something like an Asian language. You can take the same exact sounding word, but based on your inflection in tone you can mean radically different things. The alphabet to produce the words is all the same, but its the accent that’s important. The same can be said about a PTM code like the glycocode. It’s an important accent on biology.

Pars distalis-derived TSH (PD-TSH) stimulates the thyroid gland to produce thyroid hormones (THs), whereas pars tuberalis-derived TSH (PT-TSH) acts on the hypothalamus to regulate seasonal physiology and behavior. Quite literally you have the same gland producing the same Mona Lisa (protein). Except they avoid cross-talk and have very specific tissue targets. The difference: a sugar modification. Looks like those hues and accents are actually pretty important…..

And you can try to get something like a cell to overproduce an enzyme that produces a sugar structure using genetic engineering, yet it doesn’t always work because there’s a lot more systems biology governing its control.

Sure, but isn’t it pretty striking just how few bits are in the genome? And the coding portion, a fancy camera puts more bits than that in a single photo. We consume a genome’s worth of information content like it’s a corn chip. It makes you wonder if nature is smarter than we are.

“3 sugars alone that are used in biology to modify proteins can produce over 38,000 possible permutations”
Without checking your math, do you know how many of those permutations are actually produced in vivo?

Of course not all 38,000 permutations aren’t produced in vivo, but this was also in response to the number of theoretical permutations of base pairs in DNA. Let’s not say that 4^3 M possible combinations of nucleotides is impressive for DNA when there’s redundancy in the genetic code too. The information hidden in something like the glycocode is because of chemistry (an even when you remove the types of structures biology doesn’t produce the entire set of possible modifications is still massive, especially considering multiple types can be added to one single protein and they have PTMs on top of PTMs). Not only can sugars branch, they can have alpha/beta configurations. Take 2 hexoses – how many ways can you arrange them when you can include number of linkages AND alpha/betas? How many ways do you have of attaching 2 peptides together? And biology absolutely recognizes the difference. High schoolers learn the difference between polymers of beta linked glucoses and alpha linked glucoses. If you attach something like a single sialic acid in an alpha 2,3 fashion cancer has a better prognosis vs. linking it in a alpha 2,6 fashion. The latter shuts down the immune system. A protein might not have just one type of PTM like a glycan with a huge amount of combination possibilities, a protein will have multiple sites of PTMs to produce almost an infinite amount of permutations that would be theoretically possible awhen you include transformations like hydroxylations, acetylations, methylations, phosphorylations, sumoylations, ubiquitinations, etc. etc. And they are all changing dynamically.

Even solving the DNA code and producing protein crystal structures of proteins doesn’t allow you to predict when and where a PTM will occur. AFAIK, no one has solved where O-linked glycans will occur on proteins because there’s no consensus sequence. Even N-linked types of sugar modifications have consensus sequences, but there are many examples of where the same protein will sometimes have modifications at those sites while other times they don’t. How many complex diseases are the result of malfunctioning proteins that have aberrant forms of PTMs? If you looked at the gene, gene expression, or even protein levels, however, you’d assume that everything is fine because they might not have any mutations or aberrant expression at all. Changing a phosphorylation profile, however, of a cancer associated transcription factor with no mutations can induce the expression of hundreds of cancer related genes.

PTMs don’t even touch on the subject of the systems biology of signaling networks. Even cracking the genetic code really hasn’t allowed anyone to completely understand how entire networks of protein-protein interactions and protein machines behave. You find a mutated protein in a complex disease like AZ or cancer or inhibit some protein in its pathway and find no effect. Ooppps, there’s redundancy and robustness of networks.

How many complex diseases like AZ are the result of malfunctioning of the entire systems described all above ?

Some diseases like cancer (childhood leukemia, for example), were cured when people simply threw molecules together in a cocktail and ultimately screened for results. They didn’t really know how they were working or were looking for ‘targets’. I know Derrick has typed a lot on the topic of phenotypic screening, but it really gets at the heart of the idea that maybe we simply don’t know as much as we think we do about life and disease. We can, however, screen for therapies that ultimately produce the desired results, regardless of whether or not we know how they work. We were incredible successful before using this same approach before the whole genetics ‘revolution’ took over and everyone began to chase specific targets. And that’s not to downplay the importance of the targeted approach. It definitely has worked, but there are larger diseases out there that might be simply too complex and for which targeted therapies and focusing on one protein alone like Tau, b-amyloids, etc. might not work.

I’ll stick my toe in the pool once again, admitting that this isn’t my field. What if EITHER beta amyloid OR tau was sufficient? If that’s the case then knocking out either one would not suffice. You need to block both pathways. To my mind (which is admittedly not conversant with the field) this hypothesis fully explains the data supporting amyloid and the failure of those treatments to reverse pathology. It also predicts the failure of tau-only approaches. (And PLEASE – no more peroxynitrite comments. It has nothing to do with this hypothesis. Please.)

if either Tau or beta-amyloid were sufficient, then we would see three clinical populations; those with tau defects, those with beta-amyloid defects, and those with both. Some of them should respond to one treatment or to the other.

Again, not my field, but I’d bet dollars to donuts that the vast majority of patients treated in the Ph3 trials had both amyloid AND tau defects. You’d have to identify and treat a population with only one (maybe very early onset) to see the effects you’re claiming. And don’t forget that a number of these trials did have patients who responded.

On another point, Barry’s claim that Alzheimer’s could not be inflammatory in nature because so many people have been treated with NSAIDs is, of course, absurd. Inflammation is a multi-pathway disease and if NSAIDs were a cure all then there would be no rheumatoid arthritis, type 1 diabetes, etc., etc. Inflammation is clearly a viable hypothesis for Alzheimer’s and the recent data on complement and microglial involvement in pruning might well be relevant.

Drill a hole in the skull and directly instill it. Good enough for hypothesis testing purposes. Your only problem is then you have the confounding variable of trepanning. The control condition for the study would need some thought.

I must say… my mother has recently been diagnosed with Alzheimer’s and the tiny bit of hope we have is that my mother has just been enrolled in an anti Tau clinical trial. It’s quite a commitment, over two years that include infusions, PET scans, MRIs, and spinal taps. We also need to travel a distance to get her to 25+ appts. I felt we were fortunate to have her enrolled, but the comments following this blog have just left me feeling deflated.

It’s hard. On the one hand, participating in a trial, although it’s hard, is the only way that you can have hope that something new can be found. But realistically, the chances for an Alzheimer’s trial to work are low. But if we don’t run any, the chances are zero.

Not wishing to make light of the plight of those afflicted with Alzeimer’s and their families, but, to quote Wayne Gretzky, you may miss 99% of the shots you take but you miss 100% of the shots you don’t take.